Acetylcholine secreting neurons in the brain are thought to control several types of distinct behaviors. Central cholinergic dysfunction is one of the hallmarks of certain brain diseases such as Alzheimer's disease, in which cholinergic hypofunction has been suggested to affect attention and memory. The physiological roles of acetylcholine in learning, memory and attention are still poorly understood, likely because there is no model system where cholinergic hypofunction can be selectively achieved in brain regions. Our long term goal is to understand the actions of acetylcholine in brain function in mammals. We would like to understand how acetylcholine secretion controls neurochemical systems in discrete brain regions and how this affects behavior. To achieve this goal, a collection of mouse lines with deficits of acetylcholine release will be generated using gene targeting techniques and the Cre/loxP system. These mouse lines will be characterized biochemically for the consequences of lack of acetylcholine secretion, particularly in the cortex, hippocampus and striatum. Several biochemical markers and the release of acetylcholine will be assessed. Suitable mouse lines that shown brain region deficits of acetylcholine release with preserved peripheral function will be used to investigate possible roles of acetylcholine in brain function, by using distinct behavioral paradigms. This approach will allow understanding the actions of acetylcholine in memory and attention and may reveal novel physiological functions for this neurotransmitter. We envision that these mice will help to answer long standing questions on the relationship between cholinergic dysfunction and Alzheimer's disease. The research proposed will be done primarily in Brazil, at the Federal University of Minas Gerais in collaboration with Dr. Marco A.M. Prado, Associate Professor of Pharmacology in the Institute of Biological Sciences, as an extension of the grant "Genetic Analysis of Dopaminergic Reward Mechanisms" #RO1-DA131511-01.